4-hydroxybutyric acid analogs

ABSTRACT

This invention relates to novel derivatives of 4-hydroxybutyric acid and prodrugs thereof, and pharmaceutically acceptable salts of the foregoing. This invention also provides pharmaceutical compositions comprising a compound of this invention and the use of such compositions in methods of treating narcolepsy, fibromyalgia, other disorders or conditions that are beneficially treated by improving nocturnal sleep or by administering sodium oxybate.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/372,989, filed Feb. 14, 2012, which claims the benefit of U.S.Provisional Patent Application No. 61/442,451, filed Feb. 14, 2011 andU.S. Provisional Patent Application No. 61/484,296, filed May 10, 2011.The contents of the foregoing applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

4-Hydroxybutyric acid is a well-known hypnotic agent. Though itsmechanism of action is poorly understood, 4-hydroxybutyrate has beencharacterized as inhibiting polysynaptic reflexes while retainingmonosynaptic reflexes. It typically induces sleep while maintaining goodrespiration (Basil, B. et al., Br J Pharmacol Chemother, 1964, 22:318and increases delta sleep (stage 3 and stage 4) and decreasing light orstage 1 sleep (Scrima, L. et al., Sleep, 1990, 13:479; Pardi, D. andBlack, J., CNS Drugs, 2006, 20:993.

The sodium salt of 4-hydroxybutyric acid, known generically as sodiumoxybate and marketed as Xyrem®, is approved for the treatment ofexcessive daytime sleepiness and cataplexy in patients with narcolepsy.It is reported to be effective for relieving pain and improving functionin patients with fibromyalgia syndrome (Scharf, M B et al., J Rheumatol,2003, 30:1070; Russell, I J et al., Arthritis Rheum 2009, 60:299).Sodium oxybate has also been reported to be effective in alleviatingexcessive daytime sleepiness and fatigue in patients with Parkinson'sdisease, improving myoclonus and essential tremor, and reducing tardivedyskinesia and bipolar disorder (Ondo, W G et al., Arch Neurol, 2008,65:1337; Frucht, S J et al, Neurology, 2005, 65:1967; Berner, J E, JClin Psychiatry, 2008, 69:862). Sodium oxybate is in or has been inclinical trials for treatment of fibromyalgia, Parkinson's disease,obstructive sleep apnea syndrome, insomnia associated withschizophrenia, sleep initiation and maintenance disorders (chronicinsomnia), chronic fatigue syndrome, essential tremor, hemiplegia,sedative abuse and binge-eating disorder (seehttp://clinicaltrials.gov/ct2/results?term=sodium+oxybate).

The very short half life of sodium oxybate in humans (0.5-1 hour) is amajor limitation in its use. The recommended dosing schedule for4-hydroxybutyric acid is twice nightly, first upon entering bed andagain 2.5 to 4 hours later (see, e.g., FDA product label dated Nov. 13,2006 for NDA no. 021196). This schedule can be quite inconvenient to thepatient. Consequently, despite the desirable and beneficial effects of4-hydroxybutyric acid, there is a continuing need for new compounds totreat the aforementioned diseases and conditions.

SUMMARY OF THE INVENTION

This invention relates to novel derivatives of 4-hydroxybutyric acid andprodrugs thereof, and pharmaceutically acceptable salts of theforegoing. This invention also provides pharmaceutical compositionscomprising a compound of this invention and the use of such compositionsin methods of selectively inhibiting polysynaptic reflexes withoutsignificantly affecting monosynaptic reflexes, and treating narcolepsy,fibromyalgia, other disorders and conditions that are beneficiallytreated by improving nocturnal sleep or by administering sodium oxybate.

DETAILED DESCRIPTION

The term “treat” as used herein means decrease, suppress, attenuate,diminish, arrest, or stabilize the development or progression of adisease (e.g., a disease or disorder delineated herein), lessen theseverity of the disease or improve the symptoms associated with thedisease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of sodium oxybatewill inherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15;Gannes, L Z et al., Comp Biochem Physiol Mol lntegr Physiol, 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 50.1% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species that differs from a specificcompound of this invention only in the isotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 49.9% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 47.5%,less than 40%, less than 32.5%, less than 25%, less than 17.5%, lessthan 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% ofthe compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The pharmaceutically acceptable salt may also be a salt of a compound ofthe present invention having an acidic functional group, such as acarboxylic acid functional group, and a base. Exemplary bases include,but are not limited to, hydroxide of alkali metals including sodium,potassium, and lithium; hydroxides of alkaline earth metals such ascalcium and magnesium; hydroxides of other metals, such as aluminum andzinc; ammonia, organic amines such as unsubstituted orhydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers, or less than “X”% of other stereoisomers(wherein X is a number between 0 and 100, inclusive) are present.Methods of obtaining or synthesizing an individual enantiomer for agiven compound are known in the art and may be applied as practicable tofinal compounds or to starting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. Unless otherwise indicated,“stereoisomer” refers to both enantiomers and diastereomers.

The term “optionally substituted with deuterium” means that one or morehydrogen atoms in the referenced moiety may be replaced with acorresponding number of deuterium atoms.

The term “C₂₋₁₀ alkoxyalkyl” refers to a moiety of the formula—(CH₂)_(a)—O—(CH₂)_(b), wherein each of a and b is an integer between 1and 9; and the sum of a+b is an integer between 2 and 10.

Throughout this specification, a variable may be referred to generally(e.g., “each R”) or may be referred to specifically (e.g., R¹, R², R³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention provides a compound of Formula B:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is hydrogen, deuterium, —CH₂—C(O)OR^(2′) or —CH(R^(1′))—C(O)OR^(2′);

R^(1′) is C₁₋₆ alkyl, C₂₋₁₀ alkoxyalkyl, phenyl, —(C₁₋₃ alkyl)-(C₃₋₆cycloalkyl), or C₃₋₆ cycloalkyl, wherein R^(1′) is optionallysubstituted with C₁₋₃ alkyl, C₁₋₃ alkoxy, phenyl, or—O—(CH₂CH₂O)_(n)—CH₃, wherein n is 1, 2, or 3;

R^(2′) is hydrogen; deuterium; —C₁₋₄ alkyl optionally substituted withphenyl; —(C₃₋₆ cycloalkyl) optionally substituted with phenyl or methyl;—CH₂—(C₃₋₆ cycloalkyl) wherein the C₃₋₆ cycloalkyl is optionallysubstituted with phenyl; phenyl; or biphenyl;

X¹ is hydrogen, deuterium, —C(O)-indanyl, —C(O)-indenyl,—C(O)-tetrahydronaphthyl, —C(O)—C₁₋₆ alkyl, —C(O)—C₁₋₆ alkenyl,—C(O)—C₁₋₆ alkynyl, —C(O)—C₁₋₃ alkyl optionally substituted with C₃₋₆cycloalkyl, or —C(O)—C₃₋₆ cycloalkyl optionally substituted with C₁₋₆alkyl, phenyl or naphthyl; and

each Y is independently selected from hydrogen and deuterium, providedthat:

(i) when A¹ is hydrogen or deuterium, at least one Y is deuterium; and

(ii) when X¹ is hydrogen or deuterium, each Y² is deuterium, and each Y³is deuterium, then A¹ is not hydrogen or deuterium.

In one embodiment of Formula B, at least one Y is deuterium. In oneaspect of this embodiment, X¹ is other than hydrogen or deuterium.

In one embodiment of Formula B, R^(2′) is hydrogen, —C₁₋₄ alkyl, —C₃₋₆cycloalkyl, —CH₂—(C₃₋₆ cycloalkyl), phenyl or benzyl, and at least one Yis deuterium.

In a more specific embodiment of a compound of Formula B, A¹ is—CH₂—C(O)OR^(2′) or —CH(R^(1′))—C(O)OR^(2′); R^(1′) is C₁₋₄ alkyl; eachY¹ is the same; each Y² is the same; each Y³ is hydrogen; X¹ ishydrogen, —C(O)CH₃, or —C(O)CH₂Ph, provided that at least one of Y¹ andY² is deuterium. In one aspect of this embodiment, R^(2′) is —CH₃,—CH₂CH₃, or benzyl.

In another embodiment of Formula B: A¹ is hydrogen; each Y¹ is the same;each Y² is the same; each Y³ is hydrogen; and X¹ is selected from acetyland benzoyl, provided that at least one of Y¹ and Y² is deuterium. Inone aspect of this embodiment, each Y¹ is deuterium.

In another embodiment of Formula B, each Y is independently selectedfrom hydrogen and deuterium; wherein each Y¹ is the same, each Y² is thesame and each Y³ is the same, wherein at least one pair of Y isdeuterium; wherein each Y³ is deuterium, provided that: when X¹ ishydrogen or deuterium, each Y² is deuterium, and each Y³ is deuterium,then A¹ is not hydrogen or deuterium. The remainder of the variables areas defined in paragraph 25.

In one embodiment of Formula B, A¹ is —CH(R^(1′))—C(O)OR^(2′), thecompound having the structure of Formula B-II:

or a pharmaceutically acceptable salt thereof, wherein X¹, Y, R^(1′) andR^(2′) are as described above for Formula B.

In compounds of Formula B-II, the carbon atom bearing R^(1′) has achiral center. In one embodiment, the compound of Formula B-II has the(S) configuration at that chiral center as shown in Formula (S)-B-IIbelow.

In certain embodiments of compounds of Formula B, B-II and (S)-B-II,each Y¹ is the same; each Y² is the same; and each Y³ is the same, andat least one pair of Y (e.g., each Y¹; each Y²; or each Y³) isdeuterium. In one specific aspect, each Y³ is hydrogen.

Another embodiment of Formula B provides a compound wherein each Y³ ishydrogen and A¹ is —CH₂—C(O)OR^(2′), the compound having the structureshown in Formula B-III:

or a pharmaceutically acceptable salt thereof, wherein the X¹, Y andR^(2′) variables are as described above for Formula B.

In certain embodiments of compounds of Formula B-III, each Y¹ is thesame; each Y² is the same; and each Y³ is the same, and at least onepair of Y (e.g., each Y¹; each Y²; or each Y³) is deuterium. In onespecific aspect, each Y³ is hydrogen.

The present invention also provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is hydrogen, deuterium, —CH₂—C(O)OR² or —CH(R¹)—C(O)OR²;

R¹ is a C₁₋₆ alkyl, C₂₋₁₀ alkoxyalkyl, or C₃₋₆ cycloalkyl group that isoptionally substituted by an R³ group;

R³ is C₁₋₃ alkyl, C₁₋₃ alkoxy, phenyl, —O—(CH₂CH₂O)_(n)—CH₃, or-(heterocyclyl)-C₁₋₃ alkyl where the heterocyclyl moiety is a four tosix-membered ring having an oxygen ring atom;

n is 1, 2, or 3;

R² is hydrogen, deuterium, —C₁₋₄ alkyl, —C₁₋₄ alkyl-phenyl, —C₃₋₆cycloalkyl, —C₃₋₆ cycloalkyl-phenyl, —CH₂—(C₃₋₆ cycloalkyl), —CH₂—(C₃₋₆cycloalkyl)-phenyl, phenyl, or biphenyl;

X is hydrogen, deuterium, —C(O)-indanyl, —C(O)-indenyl,—C(O)-tetrahydronaphthyl, —C(O)—C₁₋₆ alkyl, —C(O)—C₁₋₆ alkenyl,—C(O)—C₁₋₆ alkynyl, —C(O)—C₁₋₃ alkyl-(C₃₋₆ cycloalkyl), or —C(O)—C₃₋₆cycloalkyl optionally substituted by C₁₋₆ alkyl, phenyl or naphthyl; and

each Y is independently selected from hydrogen and deuterium, providedthat when A is hydrogen at least one Y is deuterium.

In one embodiment of Formula I, when A is deuterium, at least one Y isdeuterium.

In one embodiment of Formula I, each Y is independently selected fromhydrogen and deuterium, provided that when A is hydrogen at least one Yis deuterium and X is not hydrogen.

Examples of the R³ heterocyclyl moiety of Formula I include oxetane,tetrahydrofuran, furan, tetrahydropyran and pyran.

In one embodiment of Formula I, R² is hydrogen, —C₁₋₄ alkyl, —C₃₋₆cycloalkyl, —CH₂—(C₃₋₆ cycloalkyl), phenyl or benzyl.

In a more specific embodiment of a compound of Formula I A is—CH₂—C(O)OR² or —CH(R¹)—C(O)OR²; R¹ is C₁₋₄ alkyl; each Y¹ is the same;each Y² is the same; each Y³ is hydrogen; X is hydrogen, —C(O)CH₃, or—C(O)CH₂Ph. In one aspect of this embodiment, R² is —CH₃, —CH₂CH₃, orbenzyl.

In another embodiment of Formula I: A is hydrogen; each Y¹ is the same;each Y² is the same; each Y³ is hydrogen; and X is selected from acetyland benzoyl. In one aspect of this embodiment, each Y¹ is deuterium.

In one embodiment of Formula I, A is —CH(R¹)—C(O)OR², the compoundhaving the structure of Formula II:

or a pharmaceutically acceptable salt thereof, wherein X, Y, R¹ and R²are as described above for Formula I.

In compounds of Formula II, the carbon atom bearing R¹ has a chiralcenter. In one embodiment, the compound of Formula II has the (S)configuration at that chiral center as shown in Formula (S)-II below.

In certain embodiments of compounds of Formula I, II and S-II, each Y¹is the same; each Y² is the same; and each Y³ is the same. In onespecific aspect, each Y³ is hydrogen.

Another embodiment of Formula II provides a compound wherein each Y³ ishydrogen and R¹ is hydrogen, the compound having the structure shown inFormula III:

or a pharmaceutically acceptable salt thereof, wherein the X, Y and R²variables are as described above for Formula I.

Table 1 shows examples of specific compounds of Formula III.

TABLE 1 Examples of Specific Compounds of Formula III Compound # X EachY¹ Each Y² R² 100 H H H CH₃ 101 H H H C₂H₅ 102 H H H CH₂C₆H₅ 103 H D HCH₃ 104 H D H C₂H₅ 105 H D H CH₂C₆H₅ 106 H H D CH₃ 107 H H D C₂H₅ 108 HH D CH₂C₆H₅ 109 Ac H H CH₃ 110 Ac H H C₂H₅ 111 Ac H H CH₂C₆H₅ 112 Ac D HCH₃ 113 Ac D H C₂H₅ 114 Ac D H CH₂C₆H₅ 115 Ac H D CH₃ 116 Ac H D C₂H₅117 Ac H D CH₂C₆H₅ 118 H H H H

In certain embodiments, the compound of Formula III is apharmaceutically acceptable salt of any one of the compounds set forthin Table 1.

In another embodiment of Formula I, the compound is a compound ofFormula IV:

or a pharmaceutically acceptable salt thereof, wherein the X, Y and Avariables are as described above for Formula I.

In one embodiment, the compound is a compound of Formula IV′

or a pharmaceutically acceptable salt thereof, wherein the X, Y and Avariables are as described above for Formula I.

Specific examples of compounds of Formula IV′ include the following:

or a pharmaceutically acceptable salt of one of IV-a, IC-b, IV-c, orIV-d.

Under certain synthetic conditions, Compounds of Formula IV′ may beprepared with an isotopic abundance at each position indicated as “D” ofat least about 75%. Under other synthetic conditions, Compounds ofFormula IV′ may be prepared with an isotopic abundance at each positionindicated as “D” of greater than about 95%.

Under certain synthetic conditions, Compounds of Formula IV-a, IV-b,IV-c, and IV-d may be prepared with an isotopic abundance at eachposition indicated as “D” of at least about 75%. Under other syntheticconditions, Compounds of Formula IV-a, IV-b, IV-c, and IV-d may beprepared with an isotopic abundance at each position indicated as “D” ofgreater than about 95%.

Under the synthetic conditions disclosed herein, the Compound of FormulaIV-b has been prepared with an isotopic abundance at each positionindicated as “D” of at least about 95%.

In one embodiment of Formula IV, the compound is a compound of FormulaIV″:

or a pharmaceutically acceptable salt thereof,

wherein A is —CH₂—C(O)OR² or —CH(R¹)—C(O)OR²;

R¹ is —C₁₋₆ alkyl; and

R² is —C₁₋₄ alkyl; and

X is hydrogen, deuterium or —C(O)—C₁₋₆ alkyl.

In one embodiment of Formula IV″, the compound is a compound of FormulaIV″-a:

or a pharmaceutically acceptable salt thereof.

In one embodiment of Formula IV″, the compound is a compound of FormulaIV″-b:

or a pharmaceutically acceptable salt thereof.

Under certain synthetic conditions, Compounds of Formula IV″ may beprepared with an isotopic abundance at each position indicated as “D” ofat least about 75%. Under other synthetic conditions, Compounds ofFormula IV′ may be prepared with an isotopic abundance at each positionindicated as “D” of greater than about 95%.

Under certain synthetic conditions, Compounds of Formula IV″-a and IV″-bmay be prepared with an isotopic abundance at each position indicated as“D” of at least about 75%. Under other synthetic conditions, Compoundsof Formula IV″-a and IV″-b may be prepared with an isotopic abundance ateach position indicated as “D” of greater than about 95%.

In one embodiment of Formula IV, the compound is a compound of FormulaIV′″

wherein X is hydrogen, deuterium or —C(O)—C₁₋₆ alkyl.

In one embodiment, X is —C(O)—C₁₋₆ alkyl.

Specific examples of compounds of Formula IV′″ include the following:

or a pharmaceutically acceptable salt of one of the foregoing.

In one embodiment the invention is directed to a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein

wherein

each Y is independently selected from hydrogen and deuterium,

R⁴ is —C₁₋₆ alkyl or C₆-C₁₀ aryl; and

X is hydrogen, deuterium or —C(O)—C₁₋₆ alkyl.

In one embodiment of formula V, if X is hydrogen, then at least one Y isdeuterium.

In one embodiment of Formula V, the compound is a compound of FormulaV-a:

In one aspect of Formula V-a, R⁴ is methyl.

In one embodiment of Formula V, the compound is a compound of FormulaV-b:

In one aspect of Formula V-b, R⁴ is methyl.

In one embodiment of Formula V, the compound is a compound of FormulaV-c:

In one aspect of Formula V-c, R⁴ is methyl.

In one embodiment of Formula V, the compound is a compound of FormulaV-d:

In one aspect of Formula V-d, R⁴ is methyl.

In one embodiment of Formula V, the compound is a compound of FormulaV-e:

In one aspect of formula V-e, R⁴ is methyl.

In another embodiment the invention provides a compound selected fromany one of

or a pharmaceutically acceptable salt thereof.

In another embodiment the invention provides the compound

or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention provides a compound selectedfrom any one of HO—CH₂—CH₂—CD₂-C(O)—O⁻Na⁺, HO—CH₂—CD₂-CD₂-C(O)—O⁻Na⁺,and HO—CH₂—CD₂-CH₂—C(O)—O⁻Na⁺.

In yet another embodiment, the invention provides a compound selectedfrom any one of HO—CD₂-CH₂—CH₂—C(O)—O⁻Na⁺, HO—CD₂-CH₂—CD₂-C(O)—O⁻Na⁺,HO—CD₂-CD₂-CH₂—C(O)—O⁻Na⁺ and HO—CD₂-CD₂-CD₂-C(O)—O⁻Na⁺. In yet anotherembodiment, the invention provides a composition comprising suchcompound. In yet another embodiment, the invention provides a method oftreating an indication disclosed herein comprising administering to apatient an effective amount of such compound.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

In one embodiment the invention provides any one of the followingcompounds, where any atom not designated as deuterium is present in itsnatural abundance:

or a pharmaceutically acceptable salt of any of the foregoing.

In one embodiment, the present invention provides a compound of Formula32:

wherein each Y is independently selected from hydrogen and deuterium. Inone aspect of this embodiment, each Y² is the same and each Y¹ is thesame.

One embodiment of Formula 32 provides a compound where each Y¹ ishydrogen. Another embodiment of Formula 32 provides a compound whereeach Y¹ is deuterium.

In one embodiment, the compound of formula 32 is a compound of Formula 3

In one embodiment, the compound of formula 32 is a compound of Formula 4

In one embodiment, the compound of formula 32 is a compound of Formula32-a:

In one embodiment, the compound of formula 32 is a compound of Formula32-b:

Under certain synthetic conditions, Compounds of Formula 32 (includingcompounds of formula 31, 3, 4, 32-a and 32-b) may be prepared with anisotopic abundance at each position indicated as “D” of at least about90%, such as at least about 95%, as determined by ¹H NMR.

In one embodiment the invention provides a compound of formula VIa

wherein:

R⁶ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₃₋₈ cycloalkyl, wherein R⁶ isoptionally substituted with C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, NR²R³ or—X—P(═O)(OR⁴)(OR⁵), wherein

X is O or a direct bond;

R⁴ and R⁵ are each independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₆₋₁₀aryl;

R² and R³ are each independently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkylor C₆₋₁₀ aryl;

or R² and R³ taken together with the nitrogen attached to R² and R³ forma three- to seven-membered heterocyclyl optionally substituted with haloand containing one nitrogen atom and optionally an oxygen atom or anadditional nitrogen atom;

and

each Y² is hydrogen or deuterium.

In one embodiment of the compound of formula VIa, each Y² is hydrogen.In another embodiment, each Y² is deuterium.

In one embodiment the invention provides a compound of formula VIb

wherein:

R⁶ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₃₋₈ cycloalkyl, wherein R⁶ isoptionally substituted with C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, NR²R³ or—X—P(═O)(OR⁴)(OR⁵), wherein

X is O or a direct bond;

R⁴ and R⁵ are each independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₆₋₁₀aryl;

R² and R³ are each independently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkylor C₆₋₁₀ aryl;

or R² and R³ taken together with the nitrogen attached to R² and R³ forma three- to seven-membered heterocyclyl optionally substituted with haloand containing one nitrogen atom and optionally an oxygen atom or anadditional nitrogen atom;

each Y² is hydrogen or deuterium; and

each Y¹ is hydrogen or deuterium.

In one embodiment of the compound of formula VI, Y¹ and Y² are the same.In one aspect of this embodiment, each Y¹ and each Y² is hydrogen. Inanother aspect of this embodiment, each Y¹ and each Y² is deuterium.

In one embodiment of the compound of formula VIb, each Y¹ is deuterium.In one aspect of this embodiment, each Y² is hydrogen.

In one embodiment the invention provides a compound of formula VII

or a pharmaceutically acceptable salt thereof, wherein

R⁶ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₃₋₈ cycloalkyl, wherein R⁶ isoptionally substituted with C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, NR²R³ or—X—P(═O)(OR⁴)(OR⁵), wherein

X is O or a direct bond;

R⁴ and R⁵ are each independently C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₆₋₁₀aryl;

R² and R³ are each independently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkylor C₆₋₁₀ aryl;

or R² and R³ taken together with the nitrogen attached to R² and R³ forma three- to seven-membered heterocyclyl optionally substituted with haloand containing one nitrogen atom and optionally an oxygen atom or anadditional nitrogen atom;

R⁷ is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₃₋₈ cycloalkyl, wherein R⁶ isoptionally substituted with C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, —C(O)OC₁₋₆alkyl optionally substituted with C₆₋₁₀ aryl, NR²R³, or hydrogen;

each Y² is hydrogen or deuterium; and

each Y¹ is hydrogen or deuterium.

In one embodiment of the compound of formula VII, Y¹ and Y² are thesame. In one aspect of this embodiment, each Y¹ and each Y² is hydrogen.In another aspect of this embodiment, each Y¹ and each Y² is deuterium.

In one embodiment of the compound of formula VIb, each Y¹ is deuterium.In one aspect of this embodiment, each Y² is hydrogen.

In one embodiment of the compound of formula VII, R⁷ is hydrogen and thecompound is a carboxylic acid. In one embodiment of the compound offormula VII the compound is the sodium salt of the acid.

Such methods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure.

Exemplary Synthesis

A convenient method for synthesizing compounds of Formula I is depictedin Scheme 1.

Compounds of this invention can readily be made by means known in theart of organic synthesis.

Scheme 1 shows a general method for making compounds of Formula I.Alkylation of the alcohol group of an appropriately deuteratedtert-butyl ester of 4-hydroxybutyric acid 10 is achieved by means knownin the art, for instance by using benzyl bromide as an alkylating agentwith potassium carbonate as a base in an aprotic solvent to produce thebenzyl ester 11. Acidolytic removal of the tert-butyl group, forinstance by using excess anhydrous hydrogen chloride dissolved in aninert solvent, produces the corresponding acid 12. Esterification of theresulting acid 12 with an appropriate ester 13 usingdicyclohexylcarbodiimide (“DCC”) with catalytic 4-dimethylaminepyridine(“4-DMAP”) produces the corresponding diester 14. The benzyl group isthen removed by catalytic hydrogenation using palladium hydroxide as thecatalyst to produce a compound of Formula I, wherein X is hydrogen.Acetylation of this compound of Formula I using an anhydride and atertiary amine base such as diisopropylethylamine (“DIPEA”) produces acompound of Formula I, where X is —C(O)—C₁-C₆ alkyl.

Scheme 2 shows a method for the regioselective deuteration of the 2position of commercially available 4-hydroxybutyric acid tert-butylester (10) to yield the 2,2-dideutero species (10-d2). Reaction with adeuterium donor such as D₂O, optionally using a co-solvent such as THF,and a base such K₂CO₃ provides 4-hydroxybutyrate compounds where each Y¹is deuterium. In order to obtain the desired level of deuteriumsubstitution, several such exchange reactions may be carried out insequence. Such a sequence may provide deuterium incorporation of atleast 90% and typically greater than 95% at each Y¹ position. Theresulting selectively deuterated compound can then be carried throughthe reaction sequence specified in Scheme 1 to produce compounds ofFormula I, wherein each Y¹ is deuterium.

Scheme 3 shows a method for selective deuterium substitution at the3-position (Y²). Deuterium substitution of commercially available benzyl4-hydroxybutyrate (20), using (CH₃)₃OD and a small amount of C₆H₅CH₂ODas deuterium donors, and a base such as K₂CO₃, produces the2,2-dideutero alcohol species 21. The oxidation of the alcohol 21 usingruthenium tetroxide under neutral conditions produces the carboxylicacid 22. Tert-butyl esterification of the carboxylic acid 22 using DCCwith a catalytic amount of 4-dimethylaminepyridine and tert-butylalcohol is followed by cleavage of the benzyl ester by catalytichydrogenation using palladium hydroxide to produce the t-butoxycarboxylic acid 23. Selective reduction of the carboxylic acid 23 usingborane in THF complex produces 3,3-dideutero-4-hydroxybutyric acidtert-butyl ester (10-3,3-d2), which can be used in Scheme 1 to producecompound of Formula I, wherein Y³ is deuterium.

As shown in Scheme 4, treatment of an appropriately deuterated succinicanhydride (30) with lithium aluminum deuteride in a manner analogous toKeay, B. A., et al., J. Org. Chem. 2007, 72, 7253-7259, followed byopening and exchange of the gamma-dideuterolactone upon treatment withsodium in methanol or deuterated methanol, and re-lactonization with anacid or deuterated acid such as HCl in H₂O or DCl in D₂O, provides anappropriately deuterated lactone (31). Ring opening to afford the sodiumsalt of a compound of Formula IV′ is accomplished by treatment withsodium hydroxide or deuteroxide and appropriately deuterated methanol,in a manner analogous to Goto, G., et al, Chem. Pharm. Bull. 1985, 33,4422-4431

Compounds of Formula IV″ wherein A is —CH₂—C(O)OR² or —CH(R¹)—C(O)OR²and X is —C(O)—C₁₋₆ alkyl may be prepared from compounds of Formula IV′as shown below:

As shown in Scheme 5, treatment of the sodium salt of a compound offormula IV′ with acetic anhydride in a manner analogous to Goto, G. etal. Chem. Pharm. Bull. 1985, 33, 4422-4431 provides an acetylated sodiumsalt which is treated with an α-hydroxy ester in a manner analogous toBettolo, R. M. et al., Helv. Chim. Acta 2005, 88, 154-159 to provide acompound of formula IV″. As one skilled in the art will readilyappreciate, a suitable anyhydride or other source of —C(O)—C₁₋₆ alkylmay be used in place of acetic anhydride in the first step, and/or anester of formula HO—CH₂—C(O)OR² may be used in the second step in placeof the α-hydroxy ester shown in Scheme 5.

By procedures similar to Schemes 4 and 5, compounds of formula IV,including IV′″, may also be obtained.

As shown in Scheme 6(a), treatment of a compound of formula IV′(obtained, for example, by treatment with dilute acid of the sodium saltof a compound of formula IV′ obtained in Scheme 5) with sulfonamideR⁴SO₂NH₂ and carbodiimidazole (CDI) provides a compound of formula V (inwhich X is acetyl). Alternatively, as shown in Scheme 6(b), treatment ofthe sodium salt of a compound of formula IV′ (obtained, for example, asshown in Scheme 5) with sulfonamide R⁴SO₂NH₂ and CDI provides a compoundof formula V (in which X is hydrogen).

Ring-opening of optionally deuterated succinic anhydride in a manneranalogous to the one disclosed in patent publication WO 2011019839provides the optionally deuterated succinic acid t-butyl monoester shownin the scheme. Anhydride formation by treatment with i-butylchloroformate followed by reduction with sodium borodeuteride affordsthe deuterated 4-hydroxybutyric acid t-butyl ester. Esterification ofthe alcohol with a suitable acylating agent R⁶C(O)X followed byhydrolysis of the t-butyl group yields 4-acyloxy butyric acid 41.

B) Synthesis of Deuterated Butanediol 42

Reductive ring-opening of optionally deuterated succinic anhydride withdeuterium over Pd/C in a manner analogous to the one disclosed inJapanese patent publication 07082190 (1995) provides deuteratedbutanediol 42.

C) Synthesis of Compound of Formula VIa

Compounds 41 and 42 in a 2:1 mole ratio are coupled in the presence ofEDC to give the compound formula Via.

b) Compounds of Formula VIb or Salts Thereof A) Synthesis of 4-AcyloxyButyric Acid 43

Ring-opening of optionally deuterated succinic anhydride in a manneranalogous to the one disclosed in patent publication WO 2011019839provides the optionally deuterated succinic acid t-butyl monoester shownin the scheme. Treatment of the monoester with t-BuOY¹ in the presenceof potassium t-butoxide accomplishes exchange at the carbon adjacent tothe ester carbonyl. Anhydride formation by treatment with i-butylchloroformate followed by reduction with sodium borodeuteride affordsthe deuterated 4-hydroxybutyric acid t-butyl ester. Esterification ofthe alcohol with a suitable acylating agent R⁶C(O)X followed byhydrolysis of the t-butyl group yields 4-acyloxy butyric acid 43.

A) Synthesis of Deuterated Butanediol 44

Reduction of 43 with lithium aluminum hydride provides deuteratedbutanediol 42.

B) Synthesis of Compound of Formula VIb

Compounds 43 and 44 in a 2:1 mole ratio are coupled in the presence ofEDC to give the compound formula VIb.

Coupling of compounds 43 and 44 in the presence of EDC gives compound45. Hydrolysis of the t-butyl group of 45 yields 46, which is coupledwith 44 in the presence of EDC to give compound 47. Hydrolysis of thet-butyl group of 47 yields 48, which is treated with R⁷OH to provide thecompound of formula III.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art.

Analogous methods to the ones shown in Schemes 1-3 for compounds ofFormula I may be used for synthesizing compounds of Formula B.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the applicablecompounds are known in the art and include, for example, those describedin Larock R, Comprehensive Organic Transformations, VCH Publishers(1989); Greene T W et al., Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley and Sons (1999); Fieser L et al., Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andPaquette L, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free pharmaceutical compositionscomprising an effective amount of a compound of Formula I (e.g.,including any of the compounds of Formulae II, (S)-II, III, IV(including IV′, IV-a, IV-b, IV-c and IV-d, IV″, IV″-a, IV″-b, IV′″-a,IV′″-c and IV′″-d herein) or Formula B, B-II, (S)-B-II or B-III, or Vincluding Va-e, or VIa, VIb, or VII or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier. The carrier(s)are “acceptable” in the sense of being compatible with the otheringredients of the formulation and, in the case of a pharmaceuticallyacceptable carrier, not deleterious to the recipient thereof in anamount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa. (17th ed. 1985).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, if a protic solvent such as water or alcohols isused to dissolve or suspend a compound of this invention in apharmaceutical composition, the solvent is preferably deuterated (e.g.D₂O, CH₃CH₂OD, CH₃CH₂OD). In these cases the proton on the hydroxygroups of the compound of Formula I or B will be partially or mostlyreplaced with deuterium. Compounds of Formula I or B comprising adeuterated hydroxy group in place of —OH are also part of the presentinvention.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thepatient, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with sodiumoxybate.

In one embodiment, the second therapeutic agent is useful in thetreatment of abnormal nocturnal sleep, and conditions beneficiallytreated by improving nocturnal sleep, such as narcolepsy, andfibromyalgia. In another embodiment, the second therapeutic agent isuseful in selectively inhibiting polysynaptic reflexes in a patientwithout significantly affecting monosynaptic reflexes.

In another embodiment, the second therapeutic agent is selected fromdual serotonin-norepinephrine reuptake inhibitors and alpha2-deltasubunit calcium channel modulators.

Examples of dual serotonin-norepinephrine reuptake include, but are notlimited to, duloxetine, milnacipran, and venlafaxine.

Examples of alpha2-delta subunit calcium channel modulators include, butare not limited to, pregabalin, gabapentin, and prodrugs thereof.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat (therapeutically orprophylactically) the target disorder. For example, to reduce orameliorate the severity, duration or progression of the disorder beingtreated, prevent the advancement of the disorder being treated, causethe regression of the disorder being treated, or enhance or improve theprophylactic or therapeutic effect(s) of another therapy. In oneembodiment, the effective amount means an amount effective to treat, ina patient in need thereof, abnormal nocturnal sleep or a conditionbeneficially treated by improving nocturnal sleep, such as narcolepsy,and fibromyalgia. In one embodiment, the amount is an amount effectivein the treatment of abnormal nocturnal sleep. In one particularembodiment, the amount is an amount effective in improving nocturnalsleep. In one embodiment, the amount is an amount effective in thetreatment of narcolepsy. In one embodiment, the amount is an amounteffective in the treatment of fibromyalgia. In one embodiment, theamount is an amount effective in selectively inhibiting polysynapticreflexes in a patient in need thereof without significantly affectingmonosynaptic reflexes. In one embodiment, the amount is an amounteffective in the treatment of excessive daytime sleepiness (EDS),cataplexy, hypnagogic hallucinations, sleep paralysis, fragmented sleep,alcohol withdrawal and dependence, Parkinson's disease, narcolepsy withcataplexy, obstructive sleep apnea syndrome, insomnia including insomniaassociated to schizophrenia, sleep initiation and maintenance disorders,chronic fatigue syndrome, essential tremor, hemiplegia in patients withalternating hemiplegia of childhood, sedative abuse, or binge eatingdisorder.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from about 0.05-2.5 mmol of a compound of Formula I (e.g.,including any of the compounds of Formulae II, (S)-II, III, IV(including IV′, IV-a, IV-b, IV-c, IV-d, IV″, IV″-a, IV″-b, IV′, IV′-a,IV′″-c and IV′″-d herein) or Formula B, B-II, (S)-B-II or B-III, or Vincluding Va-e, or pharmaceutically acceptable salt thereof/kg of bodyweight, preferably between about 0.15-1.5 mmol/kg.

In one embodiment, an effective amount of a compound of this inventioncan range from about 1.9 mmol to about 65 mmol of a compound of FormulaI (e.g., including any of the compounds of Formulae II, (S)-II, III, IV(including IV′, IV-a, IV-b, IV-c, IV-d, IV″, IV″-a, IV″-b, IV′″, IV′″-a,IV′″-c and IV′″-d herein) or Formula B, B-II, (S)-B-II or B-III, or Vincluding Va-e, or a pharmaceutically acceptable salt thereof per kg ofbody weight, preferably between about 0.02 and about 1.5 mmol/kg. In oneembodiment, the effective amount of the compound or its sodium saltranges from about 0.5 g to less than 9 g, such as from about 0.5 g toabout 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In oneembodiment, the effective amount of the compound or its sodium saltranges from about 1 g to less than 9 g, such as from about 1 g to about8 g, or to about 7 g, or to about 6 g, or to about 5 g. In oneembodiment, the effective amount of the compound or its sodium saltranges from about 2 g to less than 9 g, such as from about 2 g to about8 g, or to about 7 g, or to about 6 g, or to about 5 g. In oneembodiment, the effective amount of the compound or its sodium saltranges from about 3 g to less than 9 g, such as from about 3 g to about8 g, or to about 7 g, or to about 6 g, or to about 5 g.

In the embodiments of the invention where the compound is a compound offormula VIa, VIb, or VII VIa, VIb, or VII, an effective amount ofcompound can range from about 0.015-0.8 mmol or pharmaceuticallyacceptable salt thereof/kg of body weight.

When treating a human patient in need of improved nocturnal sleep, theselected dose is preferably administered orally from 1-2 times daily.More preferably the selected dose is administered orally once daily. Forexample, the compound or its sodium salt may be administered orally inan amount disclosed once daily. As another example, the compound or itssodium salt may be administered orally in one-half of an amountdisclosed hereinabove two times daily.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forsodium oxybate.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

According to another embodiment, the invention provides a method oftreating a disease or condition that is beneficially treated by a sodiumoxybate in a patient in need thereof, comprising the step ofadministering to the patient an effective amount of a compound of thisinvention, including a compound of Formula I (e.g., including any of thecompounds of formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b,IV-c and IV-d, IV″, IV″-a, IV″-b, IV′″, IV′″-a, IV′″-c and IV′″-dherein) or Formula B, B-II, (S)-B-II or B-III, or Formula V includingVa-e, or a composition of this invention.

In one embodiment of the method, the effective amount of the compound ofthis invention can range from about 1.9 mmol to about 65 mmol of acompound of Formula I (e.g., including any of the compounds of FormulaeII, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c, IV-d, IV″, IV″-a,IV″-b, IV″′, IV′″-a, IV′″-c and IV′″-d herein) or Formula B, B-II,(S)-B-II or B-III, or V including Va-e, or a pharmaceutically acceptablesalt thereof per kg of body weight, preferably between about 0.02 andabout 1.5 mmol/kg. In one embodiment, the effective amount of thecompound or its sodium salt ranges from about 0.5 g to less than 9 g,such as from about 0.5 g to about 8 g, or to about 7 g, or to about 6 g,or to about 5 g. In one embodiment, the effective amount of the compoundor its sodium salt ranges from about 1 g to less than 9 g, such as fromabout 1 g to about 8 g, or to about 7 g, or to about 6 g, or to about 5g. In one embodiment, the effective amount of the compound or its sodiumsalt ranges from about 2 g to less than 9 g, such as from about 2 g toabout 8 g, or to about 7 g, or to about 6 g, or to about 5 g. In oneembodiment, the effective amount of the compound or its sodium saltranges from about 3 g to less than 9 g, such as from about 3 g to about8 g, or to about 7 g, or to about 6 g, or to about 5 g.

Such diseases and conditions include, but are not limited to, abnormalnocturnal sleep, and conditions beneficially treated by improvingnocturnal sleep, such as narcolepsy, and fibromyalgia. In anotherembodiment, the method is a method to selectively inhibit polysynapticreflexes in a patient without significantly affecting monosynapticreflexes.

In another embodiment, the invention provides a method of treatingexcessive daytime sleepiness (EDS), cataplexy, hypnagogichallucinations, sleep paralysis, fragmented sleep, alcohol withdrawaland dependence, Parkinson's disease, narcolepsy with cataplexy,obstructive sleep apnea syndrome, insomnia including insomnia associatedto schizophrenia, sleep initiation and maintenance disorders, chronicfatigue syndrome, essential tremor, hemiplegia in patients withalternating hemiplegia of childhood, sedative abuse, or binge EatingDisorder.

In one particular embodiment, the method of this invention is used toimprove nocturnal sleep in a patient in need thereof.

Identifying a patient in need of such treatment can be in the judgmentof a patient or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the patient in need thereof oneor more second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with sodium oxybate. The choice of secondtherapeutic agent is also dependent upon the particular disease orcondition to be treated. Examples of second therapeutic agents that maybe employed in the methods of this invention are those set forth abovefor use in combination compositions comprising a compound of thisinvention and a second therapeutic agent.

In particular, the combination therapies of this invention includeco-administering a compound of Formula I (e.g., including any of thecompounds of Formulae II, (S)-II, III, IV (including IV′, IV-a, IV-b,IV-c and IV-d, IV″, IV″-a, IV″-b, IV′″, IV′″-a, IV′-c and IV′″-d herein)or Formula B, B-II, (S)-B-II or B-III, or V including Va-e orpharmaceutically acceptable salt thereof and a second therapeutic agentto a patient in need thereof selected from dual serotonin-norepinephrinereuptake inhibitors and alpha2-delta subunit calcium channel modulators.

In one embodiment, the second therapeutic agent is a dualserotonin-norepinephrine reuptake selected from duloxetine, milnacipran,and venlafaxine.

In another embodiment, the second therapeutic agent is an alpha2-deltasubunit calcium channel modulators selected from pregabalin, gabapentin,and prodrugs thereof.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a patient does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidpatient at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I Formula I or pharmaceutically acceptable salt thereof alone ortogether with one or more of the above-described second therapeuticagents in the manufacture of a medicament, either as a singlecomposition or as separate dosage forms, for treatment or prevention ina patient of a disease, disorder or symptom set forth above. Anotheraspect of the invention is a compound of Formula I or pharmaceuticallyacceptable salt thereof for use in the treatment or prevention in apatient of a disease, disorder or symptom thereof delineated herein.

Pharmaceutical Kits

The present invention also provides kits for use in treating abnormalnocturnal sleep, and conditions beneficially treated by improvingnocturnal sleep, such as narcolepsy, and fibromyalgia. In oneembodiment, the invention provides a kit for use in treating excessivedaytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleepparalysis, fragmented sleep, alcohol withdrawal and dependence,Parkinson's disease, narcolepsy with cataplexy, obstructive sleep apneasyndrome,

insomnia including insomnia associated to schizophrenia,

sleep initiation and maintenance disorders, chronic fatigue syndrome,essential tremor, hemiplegia in patients with alternating hemiplegia ofchildhood, sedative abuse, or binge eating disorder.

These kits comprise (a) a pharmaceutical composition comprising acompound of Formula I (e.g., including any of the compounds of FormulaeII, (S)-II, III, IV (including IV′, IV-a, IV-b, IV-c and IV-d, IV″,IV″-a, IV″-b, IV′″, IV′″-a, IV′″-c and IV′″-d herein) or Formula B,B-II, (S)-B-II or B-III, or V including Va-e, or VIa, VIb, or VII or apharmaceutically acceptable salt thereof, such as a sodium salt, whereinsaid pharmaceutical composition is in a container; and (b) instructionsdescribing a method of using the pharmaceutical composition.

EXAMPLES Example 1 Synthesis of Sodium 2,2-d₂-4-Hydroxybutanoate

Step 1. 3,3-d₂-Dihydrofuran-2(3H)-one (7)

Lactone 7 was prepared according to the procedure for the synthesis oflactone 4 (see Example 4) employing dihydrofuran-2(3H)-one to afford3,3-dideuterodihydrofuran-2(3H)-one (7) as a clear oil (4.14 g, 81%). ¹HNMR (CDCl₃, 400 MHz) δ 4.35 (t, J=7.1 Hz, 2H), 2.25 (t, J=7.1 Hz, 2H).

Step 2. Sodium 2,2-d₂-4-Hydroxybutanoate

The final product was prepared according to the procedure for thepreparation of sodium 3,3-d₂-4-hydroxybutanoate (see Example 2)employing lactone 7 to afford sodium 2,2-dideutero-4-hydroxybutanoate asa white solid (2.54 g, 88%). ¹H NMR (CDCl₃, 400 MHz) δ 3.38 (t, J=5.8Hz, 2H), 1.55 (t, J=5.8 Hz, 2H).

Example 2 Synthesis of Sodium 3,3-d₂-4-Hydroxybutanoate

Step 1. 3,3-d₂-4-methoxy-4-oxobutanoic acid (1)

A sample of 4-methoxy-4-oxobutanoic acid (4.44 g, 33.6 mmol) wasdissolved in CH₃OD (Aldrich, 99 atom % D) and concentrated under reducedpressure. This process was repeated for a total of three cycles in orderto provide 4-methoxy-4-oxobutanoic acid-OD. In a separate flask, severalsmall pieces of sodium metal (1.19 g, 51.7 mmol, washed in heptane) wereadded slowly to CH₃OD (60 mL) and allowed to stir until fully dissolved.4-Methoxy-4-oxobutanoic acid-OD (4.44 g, 33.6 mmol) was then added as asolution in CH₃OD and the reaction stirred at reflux for 20 hours. Uponcooling to room temperature the reaction was quenched with aceticacid-OD (1.50 mL, Alrich, 99 atom % D) and concentrated under reducedpressure. The resulting residue was diluted with D₂O (Cambridge IsotopeLaboratories, 99 atom % D) and acidified to pH=2 with conc. 12N DCl(Aldrich, 99 atom % D) then extracted with EtOAc (3×100 mL). The organiclayers were combined, dried (Na₂SO₄), filtered and concentrated underreduced pressure followed by azeotropic removal of acetic acid withtoluene to afford 3,3-dideutero-4-methoxy-4-oxobutanoic acid (1) as awhite solid (4.21 g, 93%). ¹H NMR (CDCl₃, 400 MHz) δ 3.70 (s, 3H), 2.68(s, 2H).

Step 2. 4,4-d₂-dihydrofuran-2(3H)-one (2)

To a solution of 1 (4.21 g, 31.4 mmol) in water (50 mL) was slowly addedNaBH₄ (10.09 g, 267 mmol). Additional water (15 mL) was then added andthe reaction stirred at room temperature for 15 hours. Upon cooling to0° C., the reaction was quenched via slow addition of 12N HCl (29 mL).Additional 12N HCl (6 mL) was then added and the reaction was stirred at110° C. for 1 hour. The reaction was then cooled to room temperature,diluted with brine and extracted with DCM (3×100 mL). The organic layerswere combined, dried (MgSO₄), filtered and concentrated under reducedpressure. The resulting oil was purified via Kugelrohr distillation toafford 4,4-dideuterodihydrofuran-2(3H)-one (2) as a clear oil (654 mg,24%). ¹H NMR (CDCl₃, 400 MHz) δ 4.33 (s, 2H), 2.47 (s, 2H).

Step 3. Sodium 3,3-d₂-4-hydroxybutanoate

To a solution of 2 (2.06 g, 23.4 mmol) in methanol (100 mL) was addedsolid sodium hydroxide (918 mg, 22.9 mmol). The reaction stirred atreflux for 5 hours then was concentrated under reduced pressure toafford sodium 3,3-dideutero-4-hydroxybutanoate as a white solid (2.75 g,92%). ¹H NMR (CDCl₃, 400 MHz) δ 6.17 (s, 1H), 3.38 (s, 2H), 2.01 (s,2H).

Example 3 Synthesis of Sodium 2,2,3,3-d₄-4-hydroxybutanoate

Step 1. 2,2,3,3-d₄-4-methoxy-4-oxobutanoic acid (5)

A solution of succinic anhydride-d4 (3.00 g, 28.8 mmol, CDN Isotopes, 98atom % D) in CH₃OD (Aldrich, 99 atom % D) was stirred at reflux for 2hours then concentrated under reduced pressure to afford2,2,3,3-tetradeutero-4-methoxy-4-oxobutanoic acid (5) as a white solid(3.45 g, 88%). ¹H NMR (CDCl₃, 400 MHz) δ 3.70 (s, 3H).

Step 2. 3,3,4,4-d₄-dihydrofuran-2(3H)-one (6)

Lactone 6 was prepared according to the procedure for the synthesis oflactone 4 (see Example 4) employing carboxylic acid 5 to afford3,3,4,4-tetradeuterodihydrofuran-2(3H)-one (6) as a clear oil (1.38 g,61%). ¹H NMR (CDCl₃, 400 MHz) δ 4.33 (s, 2H).

Step 3. Sodium 2,2,3,3-d₄-4-hydroxybutanoate

The final compound was prepared according to the procedure for thepreparation of sodium 3,3-d₂-4-hydroxybutanoate (see Example 2)employing lactone 6 to afford sodium2,2,3,3-tetradeutero-4-hydroxybutanoate as a white solid (1.77 g, 89%).¹H NMR (CDCl₃, 400 MHz) δ 3.38 (s, 2H).

Example 4 Synthesis of Sodium 2,2,4,4-d₄-4-hydroxybutanoate (IVb sodiumsalt)

Step 1. 5,5-d₂-dihydrofuran-2(3H)-one (3)

A suspension of LiAlD₄ (1.27 g, 30.0 mmol, Cambridge IsotopeLaboratories, 98 atom % D) in THF (100 mL) was stirred at reflux for 1hour then cooled to −78° C. Succinic anhydride (5.00 g, 50.0 mmol) wasthen added dropwise as a solution in THF (80 mL) and the reaction wasallowed to warm to room temperature over 1.5 hours. The reaction wasthen cooled to −20° C. and was quenched with 6M HCl (20 mL). Thereaction then stirred at room temperature for 15 hours then wassubsequently diluted with brine. The resulting solution was extractedwith MTBE (5×50 mL), dried (Na₂SO₄), filtered and concentrated underreduced pressure. The resulting oil was purified via Kugelrohrdistillation to afford 5,5-dideuterodihydrofuran-2(3H)-one (3) as aclear oil (1.75 g, 35%). ¹H NMR (CDCl₃, 400 MHz) δ 2.48 (t, J=7.8 Hz,2H), 2.24 (t, J=8.3 Hz, 2H).

Step 2. 3,3,5,5-d₄-dihydrofuran-2(3H)-one (4)

Several small pieces of sodium metal (253 mg, 11.0 mmol, washed inheptane) were added slowly to CH₃OD (20 mL) at 40° C. and allowed tostir until fully dissolved. 5,5-Dideuterodihydrofuran-2(3H)-one (3)(1.75 g, 20.0 mmol) was then added as a solution in CH₃OD (20 mL) andthe reaction stirred at reflux for 15 hours. Upon cooling to roomtemperature the reaction was quenched with acetic acid-OD (1.00 mL,Aldrich, 99 atom % D) and 12N DCl (2 drops) and subsequentlyconcentrated under reduced pressure. The resulting residue was dilutedwith CH₂Cl₂, filtered through Celite®, and concentrated under reducedpressure. The resulting residue was then dissolved in D₂O (35 mL) and12N DCl (3 mL) was added. After stirring at 110° C. for 1 hour, thereaction was cooled to room temperature, diluted with brine andextracted with CH₂Cl₂ (3×100 mL). The organic layers were combined,dried (MgSO₄), filtered and concentrated under reduced pressure. Theresulting oil was purified via Kugelrohr distillation to afford3,3,5,5-tetradeuterodihydrofuran-2(3H)-one (4) as a clear oil (536 mg,30%). ¹H NMR (CDCl₃, 400 MHz) δ 2.23 (s, 2H).

Step 3. Sodium 2,2,4,4-d₄-4-hydroxybutanoate (IVb sodium salt)

The final product was prepared according to the procedure for thepreparation of sodium 3,3-d₂-4-hydroxybutanoate (see Example 2)employing lactone 4 to afford sodium 2,2,4,4-d₄-4-hydroxybutanoate as awhite solid (1.57 g, 85%). ¹H NMR (CDCl₃, 400 MHz) δ 1.53 (s, 2H).

If desired, the above-identified deuterated 4-hydroxybutyrate sodiumsalts are converted to their corresponding esters by treatment with thecorresponding alkyl halide in the presence of an aqueous base in amanner analogous to the procedure of U.S. Pat. No. 5,250,696.

Example 5 Synthesis of Exemplary Acids and Esters of Formula IV

Exemplary compounds 51-59 and 61, the structures of which are shownbelow, may be prepared as discussed in the following examples. Instructures 51-59 and 61, “Me” is CH₃; “Et” is ethyl; “t-Bu” is t-butyl;“Bn” is benzyl; “Ac” is CH₃CO; and any atom not designated as deuteriumis present at its natural isotopic abundance.

a) 4-(tert-butoxy)-3,3-dideutero-4-oxobutanoic acid (57)

A sample of 4-(tert-butoxy)-4-oxobutanoic acid (2.00 g, 11.5 mmol) wasadded to a solution of potassium tert-butoxide (1.54 g, 13.8 mmol) intBuOD (45 mL, Cambridge Isotope Labs, 99 atom % D). The reaction stirredat reflux for 15 hours then was cooled to room temperature and quenchedwith acetic acid-OD (1.50 mL, Aldrich, 99 atom % D) and concentratedunder reduced pressure. The resulting residue was diluted with 1N HCland extracted with ethyl acetate (3×50 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated to afford4-(tert-butoxy)-3,3-dideutero-4-oxobutanoic acid (57) as a white solid(1.48 g, 73%). MS (ESI) 175.1 [(M−H)].

b) tert-butyl-2,2,4,4-tetradeutero-4-hydroxybutanoate (58)

To a solution of 57 (1.48 g, 8.41 mmol) and 4-methyl morpholine (925 μL,8.41 mmol) in THF (10 mL) at 0° C. was added isobutyl cholorformate(1.10 mL, 8.41 mmol) dropwise. The resulting slurry stirred at roomtemperature for 30 minutes then was filtered through Celite® rinsingwith additional THF (3×5 mL). The clear solution was then cooled to 0°C. and a solution of sodium borodeuteride (530 mg, 12.6 mmol, CambridgeIsotope Labs, 99 atom % D) in D₂O (15 mL, Cambridge Isotope Labs, 99atom % D) was added dropwise. The reaction was immediately diluted withD₂O (50 mL) and stirred for 5 minutes. The reaction was then dilutedwith 1N HCl (50 mL) and extracted with ethyl acetate (3×50 mL). Theorganic extracts were combined, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to affordtert-butyl-2,2,4,4-tetradeutero-4-hydroxybutanoate (58) as a clear oil(1.26 g, 91%) which was used without further purification.

c) Tert-butyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (59)

To a solution of 58 (1.26 g, 7.68 mmol), 4-methyl morpholine (1.69 mL,15.4 mmol) and DMAP (94 mg, 0.77 mmol) in THF (25 mL) was added aceticanhydride (872 μL, 9.22 mmol). The reaction stirred for 15 hours thenwas diluted with 1N HCl and extracted with ethyl acetate (3×50 mL). Theorganic extracts were combined, washed with 1N HCl, dried (Na₂SO₄),filtered and concentrated to affordtert-butyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (59) as a clear oil(1.40 g, 90%). ¹H NMR (CDCl₃, 400 MHz) δ 2.04 (s, 3H), 1.89 (s, 2H),1.44 (s, 9H).

d) 4-Acetoxy-2,2,4,4-tetradeuterobutanoic acid (61)

To a solution of 59 (1.40 g, 6.80 mmol) in DCM (8 mL) was addedtrifluoroacetic acid-OD (8 mL, Cambridge Isotope Labs, 99.5 atom % D).The reaction stirred for 2 hours then was concentrated to afford4-acetoxy-2,2,4,4-tetradeuterobutanoic acid (61) as a clear oil (1.00 g,98%). MS (ESI) 149.1 [(M−H)⁻].

e)(S)-1-Methoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate(51)

To a solution of 61 (166 mg, 1.11 mmol), (S)-methyl lactate (212 μL,2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) andN,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol)followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at roomtemperature for 15 hours then was diluted with 1N HCl and extracted withethyl acetate (3×10 mL). The organic extracts were combined, washed with1N HCl, dried (Na₂SO₄), filtered and concentrated. Residual (S)-methyllactate and N,N-dimethylacetamide were then removed under reducedpressure to afford(S)-1-methoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate(51) as a clear oil (162 mg, 62%). ¹H NMR (CDCl₃, 400 MHz) δ 5.10 (q,J=7.1 Hz, 1H), 3.74 (s, 3H), 2.05 (s, 3H), 1.96 (br s, 2H), 1.48 (d,J=7.1 Hz, 3H). MS (ESI) 237.2 [(M+H)⁺].

f) (S)-1-Ethoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate(52)

To a solution of 61 (166 mg, 1.11 mmol), (S)-ethyl lactate (255 μL, 2.22mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) andN,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol)followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at roomtemperature for 15 hours then was diluted with 1N HCl and extracted withethyl acetate (3×10 mL). The organic extracts were combined, washed with1N HCl, dried (Na₂SO₄), filtered and concentrated under reducedpressure. Residual (S)-ethyl lactate and N,N-dimethylacetamide were thenremoved under reduced pressure to afford(S)-1-ethoxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeutero-butanoate(52) as a clear oil (176 mg, 63%). ¹H NMR (CDCl₃, 400 MHz) δ 5.07 (q,J=7.1 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 2.05 (s, 3H), 1.97 (br s, 2H),1.48 (d, J=7.1 Hz, 3H), 1.27 (t, J=7.4 Hz, 3H). MS (ESI) 251.1 [(M+H)⁺].

g)(S)-1-Benzyloxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeuterobutanoate(53)

To a solution of 61 (166 mg, 1.11 mmol), (S)-benzyl lactate (357 μL,2.22 mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) andN,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol)followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at roomtemperature for 15 hours then was diluted with 1N HCl and extracted withethyl acetate (3×10 mL). The organic extracts were combined, washed with1N HCl, dried (Na₂SO₄), filtered and concentrated under reducedpressure. Residual N,N-dimethylacetamide was then removed under reducedpressure and the resulting material was purified via columnchromatography (SiO₂, 0-40% EtOAc/heptanes) to afford(S)-1-benzyloxy-1-oxopropan-2-yl-4-acetoxy-2,2,4,4-tetradeutero-butanoate(53) as a clear oil (87 mg, 25%). ¹H NMR (CDCl₃, 400 MHz) δ 7.40-7.30(m, 5H), 5.24-5.10 (m, 3H), 2.04 (s, 3H), 1.94 (br s, 2H), 1.50 (d,J=7.1 Hz, 3H). MS (ESI) 313.1 [(M+H)⁺].

h) 2-Methoxy-2-oxoethyl 4-acetoxy-2,2,4,4-tetradeuterobutanoate (54)

To a solution of 61 (166 mg, 1.11 mmol), methyl glycolate (171 μL, 2.22mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) andN,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol)followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at roomtemperature for 15 hours then was diluted with 1N HCl and extracted withethyl acetate (3×10 mL). The organic extracts were combined, washed with1N HCl, dried (Na₂SO₄), filtered and concentrated. Residual methylglycolate and N,N-dimethylacetamide were then removed under reducedpressure to afford 2-methoxy-2-oxoethyl4-acetoxy-2,2,4,4-tetradeuterobutanoate (54) as a clear oil (183 mg,74%). ¹H NMR (CDCl₃, 400 MHz) δ 4.63 (s, 2H), 3.76 (s, 3H), 2.05 (s,3H), 1.98 (br s, 2H). MS (ESI) 223.1 [(M+H)⁺].

i) 2-Ethoxy-2-oxoethyl 4-acetoxy-2,2,4,4-tetradeuterobutanoate (55)

To a solution of 61 (166 mg, 1.11 mmol), ethyl glycolate (210 μL, 2.22mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) andN,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol)followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at roomtemperature for 15 hours then was diluted with 1N HCl and extracted withethyl acetate (3×10 mL). The organic extracts were combined, washed with1N HCl, dried (Na₂SO₄), filtered and concentrated. Residual ethylglycolate and N,N-dimethylacetamide were then removed under reducedpressure to afford2-ethoxy-2-oxoethyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (55) as aclear oil (176 mg, 67%). ¹H NMR (CDCl₃, 400 MHz) δ 4.61 (s, 2H), 4.22(q, J=7.1 Hz, 2H), 2.05 (s, 3H), 1.98 (br s, 2H), 1.28 (t, J=7.1 Hz,3H). MS (ESI) 237.3 [(M+H)⁺].

j) 2-Benzyloxy-2-oxoethyl 4-acetoxy-2,2,4,4-tetradeuterobutanoate (56)

To a solution of 61 (166 mg, 1.11 mmol), benzyl glycolate (315 μL, 2.22mmol) and 4-methyl morpholine (366 μL, 3.33 mmol) in THF (5 mL) andN,N-dimethylacetamide (1.0 mL) was added EDC-HCl (320 mg, 1.67 mmol)followed by DMAP (13.6 mg, 0.111 mmol). The reaction stirred at roomtemperature for 15 hours then was diluted with 1N HCl and extracted withethyl acetate (3×10 mL). The organic extracts were combined, washed with1N HCl, dried (Na₂SO₄), filtered and concentrated. ResidualN,N-dimethylacetamide was then removed under reduced pressure and theresulting material was purified via column chromatography (SiO₂, 0-40%EtOAc/heptanes) to afford2-benzyloxy-2-oxoethyl-4-acetoxy-2,2,4,4-tetradeuterobutanoate (56) as aclear oil (163 mg, 49%). ¹H NMR (CDCl₃, 400 MHz) δ7.41-7.32 (m, 5H),5.20 (s, 2H), 4.67 (s, 2H), 2.04 (s, 3H), 1.97 (br s, 2H). MS (ESI)299.2 [(M+H)⁺].

Example 6 In Vivo Pharmacokinetic Studies

The pharmacokinetics of exemplary compounds was determined by comparisonwith 4-hydroxybutyric acid by dosing the compounds in rats according tothe following study design and sampling procedure.

Study Design:

Dosing Solution Dosing Sampling Treatment Test Dosing Animals Dose Conc.Volume Time Group Compound Route N = mg/kg mg/mL mL/kg Vehicle Points 14- IV 4 200 40 5 SWFI Predose, hydroxybutyric 2, 7, 15, 30 acid sodiumsalt min, 1, 2, and 4 hours 2 PO 4 200 40 5 SWFI Predose, 5, 15, 30 min,1, 2, 4, and 6 hours 3 IV-b sodium IV 4 200 40 5 SWFI Predose, salt 2,7, 15, 30 min, 1, 2, and 4 hours 4 PO 4 200 40 5 SWFI Predose, 5, 15, 30min, 1, 2, 4, and 6 hours 5 2,2- IV 4 200 40 5 SWFI Predose,Dideutero-4- 2, 7, 15, 30 hydroxybutanoic min, 1, 2, acid, sodium saltand 4 hours 6 PO 4 200 40 5 SWFI Predose, 5, 15, 30 min, 1, 2, 4, and 6hours SWFI: Sterile water for injectionSampling Procedure:

6.1 Sampling

Frequency: See Study Design Collection: Blood samples were collected viathe jugular cannula, placed into chilled tubes containing K₂EDTA as theanticoagulant, and kept on ice until centrifugation in a refrigeratedcentrifuge. Preparation The samples were centrifuged at a temperature of4° C., at and Storage: 3,000xg, for 5 minutes. Plasma were collectedinto a 96-well plate after centrifugation of the blood samples andfrozen on dry ice. Plasma samples and leftover formulations were storedfrozen at −60° C. to −80° C. until shipped frozen on dry ice.The results of the in vivo studies are disclosed in the following table(Table 2):

TABLE 2 CL Dose T_(max) C_(max) C_(min) ^(a) AUC_(0-∞) (mL/min/ V_(z)t_(1/2) ^(b) Compd ID (mg/kg) ROA Rat # (hr) (ug/mL) (ug/mL) (hr*ug/mL)kg) (L/kg) (hr) 4-hydroxy- 200 IV Mean — —  8′ 427 8 0.2 0.26 butyric SD— — 2 30 1 0 0.02 acid, PO Mean 0.5 150 2 170 — 0.61 sodium SD 0 45 1 50— 0.04 salt % F 40% IV-b, 200 IV Mean 76  651 5 0.3 0.63 sodium SD 16 28 0 0 0.09 salt PO Mean 0.63 151 5 260 0.94 SD 0.25 73 2 127 0.75 % F40% 2,2- 200 IV Mean 19  476 7 0.2 0.33 Dideutero- SD 19  76 1 0.1 0.124-hydroxy- PO Mean 0.63 153 1 193 0.59 butanoic (+1.1X) acid, SD 0.25 90 34 0.14 sodium salt % F 41% ^(a)2 hr for IV and 4 hr for PO^(b)calculated up to 2 hr for IV and 4 hr for PO

As shown in Table 2, the pharmcokinetics of IV-b, sodium salt wasconsiderably increased relative to 4-hydroxybutyric acid, sodium salt.This is particularly clear from a comparison of the relative values ofAUC_(0-∞) and of t_(1/2) for the two compounds.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

What is claimed is:
 1. A pharmaceutical composition comprising aneffective amount of a compound of Formula IV-a, wherein the compound ofFormula IV-a is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 2. The composition of claim 1, additionallycomprising a second therapeutic agent selected from the group consistingof a dual serotonin-norepinephrine reuptake inhibitor and analpha2-delta subunit calcium channel modulator.
 3. The composition ofclaim 2, wherein the second therapeutic agent is selected from the groupconsisting of duloxetine, milnacipran, venlafaxine, pregabalin,gabapentin, and a prodrug thereof.
 4. The composition of claim 1 whereinthe composition is pyrogen-free.
 5. The composition of claim 1 whereinthe pharmaceutically acceptable salt is a sodium salt.
 6. Thecomposition of claim 5 where the compound has an isotopic abundance ateach position indicated as “D” of at least 75%.
 7. The composition ofclaim 6 where the compound has an isotopic abundance at each positionindicated as “D” of at least 95%.
 8. The composition of claim 5 wherethe compound has an isotopic abundance at each position indicated as “D”of at least 82.5%.
 9. The composition of claim 5 where the compound hasan isotopic abundance at each position indicated as “D” of at least 90%.10. The composition of claim 5 where the compound has an isotopicabundance at each position indicated as “D” of at least 97%.
 11. Amethod of treating a disease or disorder selected from the groupconsisting of excessive daytime sleepiness (EDS), narcolepsy withcataplexy, and obstructive sleep apnea syndrome, comprising the step ofadministering to a patient in need of such treatment an effective amountof the composition of claim
 1. 12. The method of claim 11 comprising theadditional step of administering to the patient in need thereof a secondtherapeutic agent selected from the group consisting of a dualserotonin-norepinephrine reuptake inhibitor and an alpha2-delta subunitcalcium channel modulator.
 13. The method of claim 12, wherein thesecond therapeutic agent is selected from the group consisting ofduloxetine, milnacipran, venlafaxine, pregabalin, gabapentin, and aprodrug thereof.